PROJECT 1: PROJECT SUMMARY Active surveillance (AS) is an important option for prostate cancer (PC) patients to avoid overtreatment, but better biomarkers are needed to avoid recommending AS to someone who may harbor aggressive disease. The rationale for AS is that PC is diagnosed in 14% of men, of whom ~80% have clinically localized disease, >80% undergo early treatment, but only ~3% ultimately die of PC. As treatment may have side effects, AS is an alternative option that may reduce overtreatment. Men with low-risk PC are monitored, and treatment is usually recommended when the patient withdraws from AS. However, within 10 years, up to ~60% of men withdraw from AS protocols. However, the majority of patients who ?fail AS? have undiagnosed clinically- significant disease from the beginning rather than disease that ?progresses? from low to high grade. In addition, many of the patients who go on definitive therapy do so because of ?PSA anxiety.? In fact, 20-40% of AS patients are eventually found to have clinically significant disease, and the impact of delayed diagnosis remains to be determined. After delayed treatment up to 50% of patients have PSA recurrence. Some of these men develop metastases and die of PC. PC has a strong genetic component, and genome-wide association studies (GWAS) have now identified >100 single nucleotide polymorphisms (SNPs) associated with PC risk, together explaining >35% of the inherited risk. Some PC risk SNPs also have been associated with PC aggressiveness, but results have been inconsistent. We aim to clarify such results by studying germline genetic variants and AS failure. Specifically, this proposal addresses the hypotheses that: 1) AS candidates carry germline variants associated with AS failure; 2) genotyping with higher-density SNP and exome arrays will allow us to identify PC-associated variants that also impact AS failure; and 3) knowledge of germline variants in men with low-risk PC may affect treatment decisions. Our preliminary studies examine candidate germline variants associated with PC in a large set of men enrolled in AS protocols using the latest SNP and whole exome array technology. Our proposed studies leverage resources of the SPORE Genetics and AS working groups and non-SPORE AS studies as well as many non-SPORE investigators working in this field. Specific aim 1 will entail statistical analyses of the genotyping data. Specific aim 2 will validate these variants in independent AS cohorts. Specific aim 3 will use in silico approaches to map validated variants on cell signaling pathways as possible pharmaceutical targets and also will entail functional analyses of the relevant genes. Specific aim 4 will develop algorithms to identify men more likely to fail AS. This work will have translational implications, ultimately leading to 1) new biomarkers for screening and treatment decisions, 2) identifying the signaling pathway(s) involved in aggressive disease, 3) identifying pharmaceutical targets for new treatments and possibly PC prevention, and 4) advancing our understanding of genetic factors that influence PC aggressiveness.